Mode of Action of Peroxisome Proliferators as Hypolipidemic Drugs.

Hertz, Rachel; Bishara-Shieban, Janette; Bar‐Tana, Jacob

doi:10.1074/jbc.270.22.13470

Cited by 315 publications

(200 citation statements)

References 53 publications

Supporting

Mentioning

185

Contrasting

Unclassified

Order By: Relevance

“…2a) or the HNF-4␣ cognate C3P enhancer of the apoC-III gene promoter upstream of the thymidine kinase promoter (32) (Fig. 2b).…”

Section: Resultsmentioning

confidence: 99%

“…GAL4-DBD-HNF-4␣-LBD chimera, consisting of the DBD of GAL4 and the LBD (amino acids 132-410) of HNF-4␣1 wild type or respective mutants, were prepared by fusing respective rat or human HNF-4␣-LBD to the C-terminal end of yeast GAL4-DBD. CAT reporter plasmids for the full-length HNF-4␣1 consisted of the (Ϫ854/ϩ22) apoC-III gene promoter or 3 copies of the C3P enhancer of the apoC-III gene promoter upstream of the thymidine kinase promoter (32). CAT reporter plasmid for the GAL4-DBD-HNF-4␣1-LBD chimera ((UAS) 5 -CAT) consisted of 5 copies of the GAL4 binding site upstream of the adenovirus E1b promoter.…”

Section: Hnf-4␣mentioning

confidence: 99%

See 1 more Smart Citation

Rescue of MODY-1 by Agonist Ligands of Hepatocyte Nuclear Factor-4α

Hertz

Ben-Haim

Petrescu

et al. 2003

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

“…2a) or the HNF-4␣ cognate C3P enhancer of the apoC-III gene promoter upstream of the thymidine kinase promoter (32) (Fig. 2b).…”

Section: Resultsmentioning

confidence: 99%

Section: Hnf-4␣mentioning

confidence: 99%

Rescue of MODY-1 by Agonist Ligands of Hepatocyte Nuclear Factor-4α

Hertz

Ben-Haim

Petrescu

et al. 2003

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

“…The APOC3 gene harbors one DR-1 that can bind PPAR/RXR heterodimer, but its promoter responds to PPAR only in non-hepatocyte cells (26), whereas HNF4 (28) or RXR induce transactivation (26). Fibrates downregulate APOC3 gene expression probably through indirect inhibition of the HNF4 nuclear receptor (29). Alternatively, PPAR␣ activators stimulate Rev-erb␣ (30) that in turn represses APOC3 (31).…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein A5, a Crucial Determinant of Plasma Triglyceride Levels, Is Highly Responsive to Peroxisome Proliferator-activated Receptor α Activators

Vu‐Dac

Gervois

Jakel

et al. 2003

Journal of Biological Chemistry

194

138

View full text Add to dashboard Cite

The recently discovered APOA5 gene has been shown in humans and mice to be important in determining plasma triglyceride levels, a major cardiovascular disease risk factor. apoAV represents the first described apolipoprotein where overexpression lowers triglyceride levels. Since fibrates represent a commonly used therapy for lowering plasma triglycerides in humans, we investigated their ability to modulate APOA5 gene expression and consequently influence plasma triglyceride levels. Human primary hepatocytes treated with Wy 14,643 or fenofibrate displayed a strong induction of APOA5 mRNA. Deletion and mutagenesis analyses of the proximal APOA5 promoter firmly demonstrate the presence of a functional peroxisome proliferator-activated receptor response element. These findings demonstrate that APOA5 is a highly responsive peroxisome proliferator-activated receptor ␣ target gene and support its role as a major mediator for how fibrates reduce plasma triglycerides in humans.Coronary heart disease continues to be a major cause of morbidity and mortality worldwide. Several epidemiological studies established that, in addition to elevated low density lipoprotein and reduced high density lipoprotein level, elevated triglycerides (TGs) 1 constitute an independent risk factor for coronary heart disease (1, 2). In addition, hypertriglyceridemia is often associated with the metabolic syndrome that characterizes diabetes and obesity (3, 4). Therefore, the identification of factors or genes affecting triglyceride metabolism is of significant medical importance for the correction of hypertriglyceridemia and associated coronary heart disease.Apolipoproteins play a determinant role in lipoprotein metabolism and in lipid homeostasis. More specifically, the APOA1/C3/A4 apolipoprotein gene cluster is tightly linked to plasma lipid profiles. Indeed, mutations in members of this cluster have been shown to cause severe dyslipidemia and heightened atherosclerosis susceptibility (5-8). A comparative genomic characterization of the APOA1/C3/A4 gene cluster flanking regions led to the recent identification of a new apolipoprotein gene, apolipoprotein A5 (APOA5), present in both mice and humans (9). apoAV shares homology with several apolipoproteins, most prominently apoAIV, and is 368 and 366 amino acids long in mice and human, respectively. This gene appears to be predominantly expressed in the liver and resides on high density lipoprotein and very low density lipoprotein particles (9, 10).The properties of apoAV were investigated by creating human APOA5 transgenic and knock-out mice and by searching for associations between human APOA5 polymorphisms and plasma lipid parameters. The Apoa5 knock-out mice display a 400% increase in plasma triglycerides compared with wild-type mice, while APOA5 transgenics exhibit triglyceride levels corresponding to one-third of those in control mice. This determinant link between APOA5 and triglycerides was supported in several separate human studies through the consistent demonstration of associations betwe...

show abstract

“…Caco-2 cells (passages [35][36][37][38][39][40][41][42][43][44][45], used for transfection experiments, were cultured in a controlled environment (37°C, 5% CO 2 ) in Dulbecco's modified Eagle's medium, 4 mM glutamine, 1% non-essential amino acids, 100 units/ml penicillin, 100 g/ml streptomycin supplemented with 20% FCS. Medium was changed every 2 days.…”

Section: Methodsmentioning

confidence: 99%

Statin Induction of Liver Fatty Acid-Binding Protein (L-FABP) Gene Expression Is Peroxisome Proliferator-activated Receptor-α-dependent

Landrier

Thomas

Grober

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Statins are drugs widely used in humans to treat hypercholesterolemia. Statins act by inhibiting cholesterol synthesis resulting in the activation of the transcription factor sterol-responsive element-binding protein-2 that controls the expression of genes involved in cholesterol homeostasis. Statin therapy also decreases plasma triglyceride and non-esterified fatty acid levels, but the mechanism behind this effect remains more elusive. Liver fatty acid-binding protein (L-FABP) plays a role in the influx of long-chain fatty acids into hepatocytes. Here we show that L-FABP is a target for statins. In rat hepatocytes, simvastatin treatment induced L-FABP mRNA levels in a dose-dependent manner. Moreover, L-FABP promoter activity was induced by statin treatment. Progressive 5 -deletion analysis revealed that the peroxisome proliferator-activated receptor (PPAR)-responsive element located at position ؊67/؊55 was responsible for the statin-mediated transactivation of the rat L-FABP promoter. Moreover, treatment with simvastatin and the PPAR␣ agonist Wy14,649 resulted in a synergistic induction of L-FABP expression (mRNA and protein) in rat Fao hepatoma cells. This effect was also observed in vivo in wild-type mice but not in PPAR␣-null animals demonstrating the direct implication of PPAR␣ in L-FABP regulation by statin treatment. Statin treatment resulted in a rise in PPAR␣ mRNA levels both in vitro and in vivo and activated the mouse PPAR␣ promoter in a reporter assay. Altogether, these data demonstrate that L-FABP expression is up-regulated by statins through a mechanism involving PPAR␣. Moreover, PPAR␣ might be a statin target gene. These effects might contribute to the triglyceride/non-esterified fatty acid-lowering properties of statins.Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. The resulting lower intracellular cholesterol concentration after statin treatment leads to a proteolytic activation of the transcription factor sterol responsive element-binding protein-2 (SREBP-2), 1 which up-regulates several genes controlling cholesterol homeostasis, including the LDL receptor (LDLr) (1). Induction of LDLr in the liver enhances clearance of circulating LDL resulting in decreased plasma LDL-cholesterol levels. Statins also increase, at least in part via a PPAR␣-dependent mechanism (2), the level of high density lipoproteins (3, 4). As a consequence, statins improve the blood cholesterol profile and markedly reduce cardiovascular mortality and morbidity in dyslipidemic patients (5-7). Statins also influence plasma TG and NEFA levels in rats and humans (4, 8 -11) through mechanisms not yet fully elucidated. Sustained hepatic clearance of TG-rich very low density lipoproteins by the LDLr (12), statin-dependent up-regulation of the lipoprotein lipase (LPL) gene, and down-regulation of the LPL inhibitor apolipoprotein C-III (13) may all contribute to the TG-lowering effect of statins. By contrast, it is not known if statins control th...

show abstract

Mode of Action of Peroxisome Proliferators as Hypolipidemic Drugs.

Cited by 315 publications

References 53 publications

Rescue of MODY-1 by Agonist Ligands of Hepatocyte Nuclear Factor-4α

Rescue of MODY-1 by Agonist Ligands of Hepatocyte Nuclear Factor-4α

Apolipoprotein A5, a Crucial Determinant of Plasma Triglyceride Levels, Is Highly Responsive to Peroxisome Proliferator-activated Receptor α Activators

Statin Induction of Liver Fatty Acid-Binding Protein (L-FABP) Gene Expression Is Peroxisome Proliferator-activated Receptor-α-dependent

Contact Info

Product

Resources

About